The objective of this research is to understand the mechanisms controlling postpneumonectomy lung growth. Recent data support the hypothesis that lung distention (or stretch) is a primary stimulus for this phenomenon. This proposal uses a new model (sustained constant positive airway pressure in unanesthetized animals) to study the consequences of distention on lung growth without partial lung resection. Preliminary data show that this model mimics important aspects of the response to unilateral pneumonectomy. The consequences of lung distention will be investigated from complimentary physiologic/anatomic and molecular perspectives. Measurements of lung and chest w,all size and recoil, airway dimensions, alveolar architecture, lung protein and DNA contents and cellular proliferation will be used to define the influence of lung distention in growing ferrets and the stimulus-response relationship. Further studies win test the effect of lung distention in mature animals, and the long-term outcome of a period of lung distention in growing animals. In parallel with these protocols, the underlying mechanisms will be investigated by studying the influence of distention on the expression of growth factors suspected to be involved in the local control of normal lung growth. Hybridization techniques (Northern blots, RNase protection assays, in situ hybridizations) and immunohistochemistry will be used to quantitate and localize distention-associated gene expression and to characterize the role of these genes. This research has important clinical implications: CPAP has long been used to improve oxygenation in acutely in patients. This research raises the possibility that long-term CPAP or pharmacologic manipulation of this response might be used to treat a variety of lung diseases (BPD, hypoplastic lung) or to increase cellular proliferation in the lung to facilitate gene therapy, lung transplantation, or healing.